Colon cancer is the second leading cause of cancer-related death in the United States (Markowitz, S. D. (2007) N Engl J Med 356, 2195-8). An estimated 135,000 new cases of colon cancer occur each year. Although many people die of colon cancer, early stage colon cancers are often treatable by surgical removal (resection) of the affected tissue. Surgical treatment can be combined with chemotherapeutic agents to achieve an even higher survival rate in certain colon cancers. However, the survival rate drops to 5% or less over five years in patients with metastatic (late stage) colon cancer. Additionally, systemic therapies in combination with chemotherapies have been developed for the treatment of colon cancer. However, no therapies have exhibited sufficient anti-tumor activity to prolong the survival of colon cancer patients with metastatic disease with any degree of reliability.
Strategies for preventing colon cancer have focused on preventing development of colonic adenomas, the premalignant tumors that are the precursors of invasive colon cancers (Markowitz, S. D. (2007) N Engl J Med 356, 2195-8). For example, pharmacologic approaches have targeted the inhibition of COX-2, an enzyme that mediates conversion of arachidonic acid to bioactive prostaglandins, and whose expression is markedly increased in colon cancers (Markowitz, S. D. (2007) N Engl J Med 356, 2195-8; Cha, Y. I. & DuBois, R. N. (2007) Annu Rev Med 58, 239-52). Inhibitors of COX-2 such as nonsteroidal anti-inflammatory drugs (NSAID) have been shown to decrease colon adenoma development in individuals with Familial Adenomatous Polyposis (Steinbach, G. et al. (2000) N Engl J Med 342, 1946-52). For example, in individuals with non-familial sporadic colon adenomas, celecoxib reduces by 33-45% the risk of developing future adenomas, and by 57-64% the risk of developing adenomas with advanced histology (Arber, N. et al., (2006) N Engl J Med 355, 885-95; Bertagnolli, M. M. et al., (2006) N Engl J Med 355, 873-84). However, a significant proportion of individuals demonstrate resistance to the colon tumor prevention activity of NSAIDs, and the molecular mechanism underlying this resistance is largely unknown. Accordingly, a need still exists to develop methods for the successful treatment of colorectal carcinoma.